The Relationship Between Obesity and the Gradual Development of Esophageal Cancer

By: Grace Peng

04/27/2015
HN 503 (Advanced Pathophysiology of Chronic Diseases)

Abstract:
Esophageal cancer has declined within the past year in terms of incidence, but it
remains a serious condition that is currently growing in mortality rate. Squamous cell carcinoma
is the most common type of esophageal cancer worldwide, especially in underdeveloped
nations. In developed nations such as the U.S., adenocarcinoma is more prevalent and is
thought to be related to an increase in Gastrointestinal Reflux Disease (GERD), Barretts
esophagus, and especially obesity which is supported by the appearance of many biomarkers
discussed in this paper. In fact, there is evidence that obesity leads to several mechanical and
biological alterations that contribute to adenocarcinoma development. The development of hiatal
hernia or increase in intra-abdominal pressure may increase the incidence of GERD. However,
the connection between obesity is more complex than that. There are many biological
mechanisms related to insulin resistance and inflammation from increases in leptin, resistin,
IGF-1, IL-6, and NF-kB as well as a decrease in the seemingly protective adiponectin cells.
Together these factors and hormones promote cancer cell growth and proliferation as well as
decrease its cell death.

Introduction:
Esophageal cancer incidence has declined within the past year from 18,000 to 17,000
new cases but it remains a serious condition that is currently growing in mortality rate to 15,000
deaths per year. Overall the incidence of esophageal cancer has increased six fold within the
past 40 years which makes it one of the fastest growing cancers. It is the 18th most common
cancer in developed countries like United States and the 8th most common cancer in the world,
namely underdeveloped countries. Despite the treatments and therapies that are currently
available, the 5-year survival rate averages at 17% and ranges from as low as 4% to as much
as 40% depending on the level of metastasis, or growth to other organs. According to National
Cancer Institute, esophageal cancer affects 4 out of 100,000 people. The epidemiology of the
cancer has changed through time from predominantly squamous cell carcinoma to
adenocarcinoma as the new leading cause. Squamous cell carcinoma occurs anywhere along
the esophagus and is found to be associated with alcohol and smoking. Adenocarcinoma,
however, occurs strictly in the lower esophagus due to replacement of the esophagus stratified
squamous cells with columnar gland cells that are normally found in the intestine linings. This
particular form of esophageal cancer has strong associations with Gastrointestinal Reflux
Disease (GERD) and Barretts Esophagus (BE) and is well documented. Current research has
turned its focus on finding the association between obesity and adenocarcinoma as well. It is
thought that there is a positive correlation between the two conditions. Obesity has increased to
approximately 80% as of 2008 and expected to continue growing. As obesity and its
comorbidities increase, we expect the biological and mechanical changes the body undergoes
will lead to development of GERD, which may progress into Barretts Esophagus if gone
untreated, and then ultimately adenocarcinoma. The purpose of this paper is to discuss those
specific mechanical mechanisms and biomarkers that show the possible link that obesity has to
adenocarcinoma at every stage of development from GERD to Barretts Esophagus and
eventually to cancer.

Discussion:
Mechanical Alterations: Obesity to GERD
The World Cancer Research Fund estimates that approximately 35% esophageal
cancers can be attributed to obesity. In fact, there have been findings of a positive association
between BMI and esophageal adenocarcinoma cancer (EAC). On the other hand, some studies
have indicated that there is stronger correlation between BE and increased waist circumference
than with BMI, though both are attributable to obesity. Obesity contributes to EAC progression
via many mechanical alterations such a hiatal hernia and increased intra-abdominal pressure.
These alterations contribute by increasing the development of GERD symptoms and eventually
BE, both of which are important risk factors of EAC. Specifically, a hiatal hernia occurs when
instead of the esophagus, the stomach protrudes past the diaphragm entrance and this allows
food and acid to reflux into the esophagus. Over time, this may cause food and stomach acid to
be trapped in that region and cause damage to the esophagus as well as GERD. An increase in
intra-adominal pressure may also lead to gastroesophageal reflux and development of GERD.
Over time, the combination of GERD acid and bile salts results in reactive oxygen species
(ROS) production which stimulate Cyclooxygenase 2 (Cox-2) which is a pro-inflammatory
enzyme that may increase cell proliferation and inhibit apoptosis. These changes increase risk
of DNA mutations and accumulation of damaged cells which are associated with cancer
development.

Insulin and Inflammatory Pathways: GERD/BE to EAC

In normal circumstances, inflammation is a protective response to eliminate stress and
injury and initiate growth and repair. However, chronic inflammation may induce DNA damage,
favoring mutations. In addition, inflammation could activate certain factors in cancer cells and
promote its survival through cell growth. In obesity, we observe a chronic low-grade
inflammation which is indicated by an increase in C-reactive proteins that are released at the

onset of inflammation due to infiltration of macrophages into adipose tissue. There are three
mechanisms involved in the initiation of this infiltration: 1) cells undergo hypoxia, or inadequate
oxygen, since angiogenesis cannot keep up with the expansion, 2) Endoplasmic Reticulum
stress due to excessive accumulation of fat and eventually cell death known as apoptosis, and
3) excessive release of free fatty acids that activate inflammatory pathways. These actions,
especially the second one, draw in macrophages to come and clear out the newly dead cells
and it is the presence of these white blood cells then trigger more pro-inflammatory cytokines.
We also often see an accumulation in free fatty acid concentration in obese individuals
which negatively affects the bodys insulin sensitivity. During an insulin resistant state, insulins
action on glucose is attenuated but it continues to promote protein synthesis, cell growth,
survival, as well as increase insulin-like-growth factors (IGF-1) that work in conjunction with
insulin to increase cell proliferation. Furthermore, inflammation increases IGF-1 while downregulating IGF-1 binding proteins (IGFBP) and preventing IGF-1 from binding. This action
further increases IGF-1 serum levels and leads to the aforementioned cell proliferation and
increases cancer risk.
Aside from increasing insulin resistance, chronic inflammation may promote cancer
progression by over-expression of various pro-inflammatory cytokines such as the
aforementioned IGF-1, TNF-alpha ((tumor necrosis factor alpha), and IL-6 (Interleukin-6). Part
of TNF-alphas main functions is to activate NF-kB (nuclear factor kappa-light-chain-enhancer of
activated B cells). This particular factor specializes in dysregulation of apoptosis, promoting cell
proliferation, and increasing nitric oxide, which is a known relaxing factor. With accumulation of
nitric oxide, we may see relaxation of the esophageal sphincter, development of GERD, and
increased risk of EAC. In fact, studies have shown that through the progression from GERD to
BE and EAC, we may see correlative increase in NF-kB levels. TNF-alpha may also inhibit
PPAR-, which is an important regulator of fatty acid and glucose metabolism. Inhibition of such
a vital receptor may further increase the individuals insulin resistance and any downstream

effects. In addition to increasing insulin resistance, IL-6 upregulates a protein called vascular
endothelial growth factor (VEGF) that primarily induces angiogenesis, which is a physiological
process that simulates new blood vessel formation from pre-existing vessels and thus providing
all the necessary nutrients to any existing cancer cells.

Adiposity and Regulatory Adipokines: GERD/BE to EAC

Aside from the mechanical alterations from obesity, there are a significant number of
biological mechanisms that result from obesity and may ultimately contribute to the progression
of BE from GERD and these include adiponectin, leptin, and resistin which are all adipose tissue
specific. Leptin is most well-known for its effect on the appetite. Normally when we eat,
adipocytes release leptin into the circulation. The brain picks up on the increased levels and
responds by decreasing appetite. In obesity we see an increase leptin resistance, possibly due
to levels passing a certain threshold and becoming less effective. With leptin circulating, there is
an increase in activation of NF-kB via various intermediary cytokines (STAT-3, p38-MAPK, etc.).
This pathway leads to an overall decrease in apoptosis and increase in tumor cell proliferation,
survival, and migration. The resistin hormone is another adipocyte-specific adipokine that is
stimulated by the chronic inflammation and acts directly on adipose and liver tissues, reducing
their insulin sensitivity and increasing serum insulin levels, which will be further discussed in a
subsequent section.
Unlike leptin and resistin, adiponectin levels tend to decrease with the increase in
adiposity seen in obesity. Under normal circumstances, adiponectin induces glucose uptake and
fatty oxidation, inhibits many pro-inflammatory cytokines that are important for cell signaling
such as NF-kB, IL-6, and TNF-alpha, and decreases fat accumulation, endothelial adhesion
molecules, and foam cell formation. However when adiponectin levels decline and free fatty acid
increase, we expect to see a significant increase in the release of pro-inflammatory cells which
put the obese individuals in a chronically inflamed state. From this, we can deduce that

adiponectin appear to have protective effects against the adenocarcinoma. However, the role of
adiponectin may be more complicated than we thought. Instead of protecting against
inflammation and cancer, high levels of adiponectin present in pre-diagnosed GERD individuals
could in fact increase the risk of BE and adenocarcinoma. In fact, there are three main isoforms
of adiponectin: low, middle, and high molecular weight adiponectin (LMW, MMW, and HMW
respectively). Both the LMW and MMW are shown to inhibit IL-6, decrease obesity, and are antiinflammatory. Recent research has shown that high levels of LMW adiponectin are associated
with lower odds of BE development. On the other hand, HMW is seen to promote proinflammatory cytokine IL-6 and may be linked to obesity, suggesting that not all adiponectin is
protective and the levels of each form determines the likelihood of cancer progression.

Biological Alterations: Microbiome

The human microbiota is a community of microorganisms that colonize at various sites
throughout the body such as the mouth and the intestines. Under normal conditions, the
microbiome aids in digestion processes, may help make vitamins that are not normally present
in the body otherwise, and supplements the immune system by competing with pathogens in the
gut. The microbiome in the esophagus specifically is suspected to have been deposited
transiently through swallowing or from the stomach when there is reflux, which leads us to the
discussion of microbiome and EAC development. Studies using cultivation techniques have
found two main types of esophageal microbiome. Type 1 is found mostly in a healthy
esophagus and contains mostly aerobic gram-positive bacteria. Type 2 is seen more in
esophagitis, BE, and EAC and consists of anaerobic gram-negative bacteria that may contain
high levels of an endotoxin known as lipopolysaccharides (LPS). Not only has LPS been linked
to obesity, it is suspected to be a causative factor in the development of obesity and insulin
resistance. In regards to the link with EAC, it is believed to slow gastric emptying resulting in
higher intra-abdominal pressure, which we know to increase the prevalence of GERD. LPS also

induces ROS Production, which we know may increase downstream cell proliferation, and
activation of toll-like receptor 4 (TLR-4). TLR-4 plays an important role in pro-inflammation by
activating NF-kB cells which increases nitric oxide levels and relaxation of muscles and the
gastroesophageal sphincter.

Conclusion:
A large number of studies have displayed strong association between the presence of
GERD/BE and development of adenocarcinoma, which has become the leading cause of
esophageal cancer worldwide. With obesity increasing in the world, especially in developed
countries like the United States, researchers have shifted their focus on establishing the
connection between obesity and EAC, whether it is through increasing GERD or BE or simply
providing a proliferative environment for cancer cells. Studies have shown that with obesity, we
mainly see mechanical alterations in the intra-abdominal pressure and appearance of a hiatal
hernia which may increase the prevalence of GERD. Gone untreated, GERD may develop into
BE or even EAC. However, the relationship between obesity and EAC is more complicated than
mechanical alterations. There are several secondary biological factors that come into play and
may indirectly progress cancer development. Chronic inflammation and insulin resistance that is
seen in obesity appears to play key roles in downregulating apoptosis while upregulating proinflammatory cytokines and growth factors, all of which increases the likelihood of generating
mutated cells as well as facilitate their growth and survival. A new area of research in the
microbiome of GERD/BE patients find that these individuals display an increase in type 2 cells
that are high in lipopolysaccharides, This particular endotoxin has strong associations with
obesity and is suspected to increase the incidence of GERD as well as the risk for developing
EAC. As you can see, obesity appears to play a large role in every stage of EAC development,
whether it is through increasing the incidence of GERD or providing an ideal environment for
cancer cell growth and proliferation. Although these findings indicate that obesity may increase

the development of esophageal cancer, it is just as possible that the same pro-inflammatory and
growth-promoting mechanisms can contribute to the progression of various other cancers.
Overall, the general recommendations for preventing and treating esophageal cancer include
managing ones weight, controlling the inflammation and GERD, and possibly improving the gut
microbiota through diet and exercise. Specifically, it is recommended to increase fresh
vegetables, fruits, quality protein, as well as pre- and pro-biotics in the daily diet.
In regards to the esophageal microbiome, are there possibilities for microbiome types beyond
type 1 and 2 and how would this effect the development of EAC? Is it possible to change the
microbiome as a curative method for GERD in order to prevent EAC? And are there other ways
that EAC could develop other than through the presence of GERD or BE? These are some
questions that require further studies and research.

References:
1. Alexandre, L., E. Long, and I. L. Beales. "Pathophysiological Mechanisms Linking
Obesity and Esophageal Adenocarcinoma." World journal of gastrointestinal
pathophysiology 5.4 (2014): 534-49. Web.
2. Almers, L. M., et al. "Adiponectin may Modify the Risk of Barrett's Esophagus in Patients
with Gastroesophageal Reflux Disease." Clinical gastroenterology and hepatology : the
official clinical practice journal of the American Gastroenterological Association (2015)
3. Cani P, Amar J, Iglesias M, Poggi M, Knauf C, Bastelica D, Neyrinck A, et al. "Metabolic
Endotoxemia Initiates Obesity and Insulin Resistance." Diabetes 56 (2007): 1761-1772.
4. Che, Fredrick, et al. "Prevalence of Hiatal Hernia in the Morbidly Obese." Surgery for
Obesity and Related Diseases 9.6(2013): 920-4. . ScienceDirect.
5. Corley D, Kubo A, Levin T, Block G, Hab L. "Abdominal Obesity and Body Mass Index
as Risk Factors for Barretts Esophagus." Gastroenterology 133 (2007): 34-41.
6. Doyle SL, Donohoe CL, Finn SP, Howard JM, Lithander FE, Reynolds JV, Pidgeon GP,
Lysaght J. "IGF-1 and its Receptor in Esophageal Cancer: Association with
Adenocarcinoma and Visceral Obesity.." American Journal of Gastroenterology 107.2
(2012): 196-204.
7. Duggan C, Onstad L, Hardikar S, Blount P, Reid B, and Vaughan T. "Association
between Markers of Obesity and Progression from Barretts Esophagus to Esophageal
Adenocarcinoma Adenocarcinoma." Clinical Gastroenterology and Hepatology 11.8
(2013): 934-43.
8. Gonzalez-Quintela A, Alonso M , Campos J , Vizcaino L , Loidi L , Gude F.
"Determinants of Serum Concentrations of Lipopolysaccharide-Binding Protein (LBP) in
the Adult Population: The Role of Obesity." Plos one 8.1 (2013): 1-8.
9. Kauppila, J. H., and K. S. Selander. "Toll-Like Receptors in Esophageal Cancer."
Frontiers in immunology 5 (2014): 200. Web.
10. Luo A, Zhang Y, Li F, He J, Ding H, Yan L, Cheng H. "Resistin Induces Insulin
Resistance by both AMPK-Dependent and AMPK-Independent Mechanisms in HepG2
Cells." Endocrinology 36 (2009): 60-9. Print
11. Ryan, Aoife M., et al. "Obesity, Metabolic Syndrome and Esophageal Adenocarcinoma:
Epidemiology, Etiology and New Targets." Cancer Epidemiology 35.4 (2011): 309-19. .
ScienceDirect.
12. Sugerman, Harvey J. "Effects of Increased Intra-Abdominal Pressure in Severe
Obesity." Surgical Clinics of North America 81.5 (2001): 1063-75. . ScienceDirect.
13. Varela, J. Esteban, Marcelo Hinojosa, and Ninh Nguyen. "Correlations between IntraAbdominal Pressure and ObesityRelated Co-Morbidities." Surgery for Obesity and Related Diseases 5.5 (2009): 524-8. .
ScienceDirect.

14. Yang, L., et al. "Microbiome in Reflux Disorders and Esophageal Adenocarcinoma."
Cancer journal (Sudbury, Mass.) 20.3 (2014): 207-10. Web.